Teneurins are a family of type II transmembrane proteins originally discovered in Drosophila. The first member was Ten-a (Baumgartner and Chiquet-Ehrismann (1993) Mech Dev 40: 165-76; Minet and Chiquet-Ehrismann (2000) Gene 257: 87-97), which was found in a search for Drosophila homologues of tenascins and shares with this protein family the same type of EGF-like repeats. The second member of the teneurin family, Drosophila Ten-m/Odd oz (Odz; Baumgartner et al. (1994) Embo J 13: 3728-40) is expressed in seven stripes during the blastoderm stage of early embryos. Mutational analysis showed that ten-m/odz is a member of the “pair-rule” gene family and encodes for an extracellular protein having a central role in determining the segmentation of the embryo. The expression pattern in the developing embryos and the adult fly suggest further important activities of this protein in later developmental processes since its presence often coincides with locations of morphogenetic cell movements, in particular, during gastrulation, the development of the tracheal system, on pioneering axons and in the developing eye (Baumgartner et al. (1994) Embo J 13: 3728-40); (Levine et al. (1994) Cell 77: 587-98); (Levine et al. (1997) Dev Dyn 209: 1-14).
Vertebrates contain four ten-a/ten-m homologues, termed ten-m1-4 (Oohashi et al. (1999) J Cell Biol 145: 563-77), odz1-4 (Ben-Zur et al. (2000) Dev Biol 217: 107-20), or teneurin 1-4 (Minet and Chiquet-Ehrismann (2000) Gene 257: 87-97), respectively. A recent study presented two new members of this family of proteins in chicken, namely, teneurin-1 and teneurin-2. Both the Drosophila and chicken proteins are expressed in early stages of embryonic development, in particular, in the developing nervous system and suggest an interaction or teneurin-2 with the cytoskeleton. Expression of recombinant teneurin-2 in a neuroblastoma cell line appears to lead to filopodia formation and enlarged growth cones (Rubin et al. (1999) Dev Biol 216: 195-209).
Mouse DOC4, the first vertebrate member of the teneurin family, was identified in a screen for proteins that were expressed in response to perturbation of protein folding in the endoplasmic reticulum (Wang et al. (1998) Embo J 17, 3619-30). Mouse DOC4 and all other vertebrate teneurins identified—namely, the mouse teneurins ten-m1-4/odz1-4 (Oohashi et al. (1999) J Cell Biol 145: 563-7); (Ben-Zur et al. (2000) Dev Biol 217: 107-20), the rat teneurin-2 orthologue, neurestin (Otaki and Firestein (1999) Dev Biol 212: 165-81), the chicken teneurins-1, -2 and -4 (Minet et al. (1999) J Cell Sci 112: 2019-32); (Rubin et al. (1999) Dev Biol 216: 195-209); (Tucker et al. (2000) Mech Dev 98, 187-91); (Tucker et al. (2001) Dev Dyn 220: 27-39) and the zebrafish Ten-m3 and Ten-m4 (Mieda et al. (1999) Mech Dev 87, 223-7)—were found to be prominently expressed in specific regions of the central nervous system.
Except for transcript localization by in situ hybridization in the nervous system and the possible involvement of teneurin-2 in the organization of the actin cytoskeleton in neuroblastoma cells, very little is known about the distribution and function of teneurins. Teneurins are known to be transmembrane proteins and are postulated to be involved in signal transduction. It has been suggested that teneurins could function as receptor proteins transmitting signals to the cell interior upon homo- or heterophilic binding of a ligand or as a membrane-bound ligand. Teneurin-2 is thought to be cleaved at the cell membrane either releasing a large part of the extracellular domain from the cell membrane, which could act as a soluble ligand or cleavage could occur after ligand binding and result in signal transduction (Rubin et al., Developmental Biology, 216, 195-209, 1999).
One potential scenario by which transmembrane proteins can fulfill their role as signaling molecules is by a mechanism recently described as regulated intramembrane proteolysis (RIP; reviewed in Brown et al. (2000) Cell 100, 391-98). RIP involves at least two cleavage steps in and at the membrane resulting in a soluble cytoplasmic part, which is translocated to the nucleus where it participates in transcription (Ebinu and Yankner (2002) Neuron 34(4):499-502. RIP is known to control diverse cellular and developmental processes. It is well known, however, that transmembrane proteins can initiate signal transduction by alternative mechanisms, such as ligand binding, receptor binding, and signaling through kinase/phosphatase cascades, etc. Indeed, Drosophila ten-m was postulated to modulate the activity of the Drosophila pair-rule gene, Odd-paired (opa) protein via a signal transduction cascade (Baumgartner et al., 1994, EMBO J. 13: 3728-3740), although a similarity between the intracellular cleavages of Odz have been linked to those of notch (Dgany and Wides, Biochem J. (2992) 363:633-643). In addition, some evidence show that a portion of Odz might translocate to the nucleus (Bagutti et al. 2003, Kenzelmann et al. 2008). Furthermore, the extracellular domain of mouse Ten m1 was found to exhibit homophilic binding and thereby inititate a signal transduction pathway (Oohashi et al., 1999).